title: A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase.
abstract: Sirtuin 2 (SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of cholesterol biosynthesis in an in vitro Huntington's disease model. This study sought to identify the first brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models. Using biochemical sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and drug development, targeting metabolic dysfunctions in CNS disorders where abnormal cholesterol homeostasis is implicated.
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: David M
authors.initials: DM
authors.lastname: Taylor
authors.forename: Uma
authors.initials: U
authors.lastname: Balabadra
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Sarah
authors.initials: S
authors.lastname: Meade
authors.forename: Allison
authors.initials: A
authors.lastname: Amore
authors.forename: Michele M
authors.initials: MM
authors.lastname: Maxwell
authors.forename: Steven
authors.initials: S
authors.lastname: Reeves
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Philip A S
authors.initials: PA
authors.lastname: Lowden
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008959:Models, Neurological; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010539:Permeability; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D002784:Cholesterol; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2